Ovarian cancer is the ninth most common cancer, and has the fifth highest mortality for cancers among women in the United States (American Cancer Society Statistics, 2012). As ovarian cancer symptoms tend to develop later in disease progression, most cases are advanced at diagnosis and have spread outside the ovary. Nearly all ovarian cancer patients receive a combination chemotherapy of cisplatin and/or carboplatin. Although the majority of patients with OVCA demonstrate remarkable sensitivity to platinum-based chemotherapy during primary therapy, the majority eventually develop platinum-resistant, recurrent disease (Baker, Salvage therapy for recurrent epithelial ovarian cancer. Hematol Oncol Clin North Am 2003; 17:977-988; Hansen, et al., New cytostatic drugs in ovarian cancer. Ann Oncol 1993; 4 Suppl 4:63-70).
The development of chemoresistance dramatically affects survival for patients with cancer, and as such, targeted therapies that increase chemo-sensitivity offer the potential to significantly improve outcome. The clinical consequences of acquired chemoresistance are exemplified by the high mortality of patients with advanced-stage ovarian cancer (OVCA). Traditionally, resistance can only be determined retrospectively after patients have undergone therapy. Once platinum-resistance has developed, few active therapeutic options exist and patient survival is generally short-lived (Herrin and Thigpen, Chemotherapy for ovarian cancer: current concepts. Semin Surg Oncol 1999; 17:181-188). In this context, platinum resistance is frequently viewed as a surrogate clinical marker for more generic chemoresistance, and it is likely that defining the molecular changes that drive the evolution of the platinum-resistant phenotype will contribute to a broader understanding of human cancer chemoresistance.
Changes in cellular drug efflux, increased cellular glutathione levels, increased DNA repair, and drug tolerance have all been shown to contribute to platinum resistance (Godwin, et al., High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proc Natl Acad Sci USA 1992; 89:3070-3074; Johnson, et al., Increased platinum-DNA damage tolerance is associated with cisplatin resistance and cross-resistance to various chemotherapeutic agents in unrelated human ovarian cancer cell lines. Cancer Res 1997; 57:850-856; Johnson, et al., Relationship between platinum-DNA adduct formation and removal and cisplatin cytotoxicity in cisplatin-sensitive and -resistant human ovarian cancer cells. Cancer Res 1994; 54:5911-5916). More recently, genomic studies have defined gene expression signatures that may discriminate between cancers that are innately chemo-sensitive versus chemo-resistant (Benedetti, et al., Modulation of survival pathways in ovarian carcinoma cell lines resistant to platinum compounds. Mol Cancer Ther 2008; 7:679-687; Dressman, et al., An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer. J Clin Oncol 2007; 25:517-525; Jazaeri, et al., Gene expression profiles associated with response to chemotherapy in epithelial ovarian cancers. Clin Cancer Res 2005; 11:6300-6310). However, the genome-wide expression changes associated with the transition of a cancer cell from chemo-sensitive to chemo-resistant are less clear, and the discrete biologic pathways that drive the process are unknown.
Outcomes for women with ovarian cancer could be improved by the identification of biomarkers capable of identifying resistant tumors and better therapies for treating them. Moreover, how these pathways influence clinical outcomes and their potential as therapeutic targets remain to be defined. As such, improved diagnostics are needed to identify likely chemotherapeutic-resistant cancers and novel targets for therapeutic approaches.